Our understanding of early anti-viral mechanisms in the cervico-vaginal compartment that may reduce HIV-1 or SIV infectivity in the absence IgG-mediated or CD8 T-cell responses remains incomplete and is the basis for this proposal. Evidence for resistance to infection in highly HIV-exposed women that remain seronegative (exposed sero-negative, ESN) in presence of anti-HIV responses is also supported by non-human primate (NHP) models where repeated low-dose cervico-vaginal challenges in Rhesus macaques can result in a refractory state that can only be overcome by increased infectious doses or by-pass of the mucosal micro- environment (e.g. intravenous viral challenge). Our preliminary data now shows for the first time that repeated cervico-vaginal exposures to SIV in the NHP can result in an increase in innate effector cell infiltrates including (1) plasmacytoid dendritic cells expressing IFN-a as a potential inductive factor associated with the local increase in tissue APOBEC 3G expression, and (2) CD68 macrophages infiltrates among Fc-receptor bearing cells. We will test the hypothesis that uninfectious viral exposures in the female cervico-vaginal compartment can induce an innate/IgA mechanism mediating a state of reduced mucosal infectivity. Specifically, we will: 1. Determine the presence of local cellular cervical tissue infiltrate, IFN-mediated gene expression, and mucosal anti-HIV IgA antibody responses in 3 well-defined groups of women with differential exposure risk based on sexual activity/partners. 2. Determine if repeated cervico-vaginal exposures to non-infectious SIV E660 exposures induce a persistent innate cellular infiltrate (plasmacytoid DCs, NK, macrophages) that in combination with mucosal SIV-specific IgA antibody levels decreases mucosal infectivity SIV mac251. This proposal represents a collaborative effort between The University of Puerto Rico, Nebraska University, University of Minnesota, Duke University, University of Massachusetts, Tulane University, National Cancer Institute, and The Wistar Institute.